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1.  Expression of matrix metalloproteinases 1, 3, and 9 in degenerated long head biceps tendon in the presence of rotator cuff tears: an immunohistological study 
Background
Long head biceps (LHB) degeneration, in combination with rotator cuff tears, can be a source of chronic shoulder pain. LHB tenotomy reduces pain and improves joint function although the pathophysiological context is not well understood. Tendon integrity depends on the extracellular matrix (ECM), which is regulated by matrix metalloproteinases (MMP). It is unclear which of these enzymes contribute to LHB but we chose to study MMP 1, 3, and 9 and hypothesized that one or more of them may be altered in LHB, whether diagnosed preoperatively or intraoperatively. We compared expression of these MMPs in both LHB and healthy tendon samples.
Methods
LHB samples of 116 patients with degenerative rotator cuff tears were harvested during arthroscopic tenotomy. Patients were assigned to 4 groups (partial thickness tear, full thickness tear, cuff arthropathy, or control) based upon intraoperative findings. Partial and full thickness tears were graded according to Ellman and Bateman's classifications, respectively. MMP expression was determined by immunohistochemistry.
Results
MMP 1 and 9 expression was significantly higher in the presence of rotator cuff tears than in controls whereas MMP 3 expression was significantly decreased. MMP 1 and 9 expression was significantly higher in articular-sided than bursal-sided partial thickness tears. No significant association was found between MMP 1 and 9 expression and full thickness tears, and the extent of the cuff tear by Bateman's classification.
Conclusion
Increased MMP 1 and 9 expression, and decreased MMP 3 expression are found in LHB degeneration. There is a significant association between the size and location of a rotator cuff tear and MMP expression.
doi:10.1186/1471-2474-11-271
PMCID: PMC2998463  PMID: 21108787
2.  The relevance of long head biceps degeneration in the presence of rotator cuff tears 
Background
Long head biceps (LHB) degeneration in combination with rotator cuff tears can be a source of chronic shoulder pain. LHB tenotomy is an approved surgical procedure for pain reduction and improvement of joint function, however, the pathophysiology of LHB degeneration is not fully understood. In the literature, neoangiogenesis in tendon tissue has previously been shown to be associated with tendon degeneration. Vascular Endothelial Growth Factor (VEGF) is an important inducer of neoangiogenesis. The hypotheses are first that an elevated VEGF expression and vessel density can be found in degenerated LHB tissue and second that there is a relation between VEGF expression, vessel density and the different types of rotator cuff tears.
Methods
LHB samples of 116 patients with degenerative rotator cuff tears were harvested during arthroscopic tenotomy. The samples were dehydrated and paraffin embedded. VEGF expression was determined using immunohistochemistry. Vessel density and vessel size were determined on Masson-Goldner stained tissue sections. On the basis of intraoperative findings, patients were assigned to 4 different groups (control group, partial thickness rotator cuff tear, full thickness rotator cuff tear and cuff arthropathy). Partial thickness rotator cuff tears were classified according to Ellman grade I-III, full thickness rotator cuff tears according to Bateman's classification (grade I-IV). The control group consisted of eight healthy tendon samples.
Results
VEGF expression in the LHB was significantly higher in the presence of rotator cuff tears than in healthy tendons (p < 0.05) whereas vessel density and vessel size were significantly higher in the LHB of patients with cuff arthropathy (p < 0.05). Furthermore, there was significantly higher VEGF expression in LHB samples from patients with articular-sided compared to bursal-sided partial thickness rotator cuff tears (p < 0.05). No significant dependence was found between VEGF expression, vessel size and vessel density in LHB of patients with full thickness rotator cuff tears and the extent of the cuff tear following Bateman's classification.
Conclusion
Elevated VEGF expression can be detected in degenerated LHB tissue. The quantity of VEGF expression and vessels are related to the extent of LHB degeneration.
doi:10.1186/1471-2474-11-191
PMCID: PMC2936349  PMID: 20799939
3.  Neutrophil Collagenase, Gelatinase and Myeloperoxidase in Tears of Stevens-Johnson Syndrome and Ocular Cicatricial Pemphigoid Patients 
Ophthalmology  2013;121(1):79-87.
Objective
To investigate the levels of matrix metalloproteinases (MMPs), myeloperoxidase (MPO) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in tears of patients with Stevens-Johnson syndrome (SJS) and ocular cicatricial pemphigoid (OCP).
Design
Prospective non-interventional cohort study.
Participants
Four SJS patients (7 eyes), 19 OCP patients (37 eyes) and 20 post-phacoemulsification healthy controls (40 eyes).
Methods
Tear washes were collected from all patients and were analyzed for levels of MMP-2, -3, -7, -8, -9, -12, MPO and TIMP-1 using multi-analyte bead-based enzyme-linked immunosorbent assays (ELISA). Total MMP activity was determined using a fluorimetric assay. Correlation studies were performed between the various analytes within study groups.
Main Outcome Measures
Levels of MMP-2, -3, -7, -8, -9, -12, MPO and TIMP-1 (in ng/µg protein), total MMP activity (in relative fluorescent units/min/µg protein) in tears, MMP-8/TIMP-1, MMP-9/TIMP-1 ratios and the correlations between MMP-8 and MMP-9 and each MMP and MPO.
Results
MMP-8, MMP-9 and MPO levels were significantly elevated in SJS and OCP tears (SJS > OCP) when compared to controls. MMP activity was highest in SJS while OCP and controls showed lower and similar activities. TIMP-1 levels were decreased in SJS and OCP when compared to controls with OCP levels reaching significance. MMP-8/TIMP-1 and MMP-9/TIMP-1 ratios were markedly elevated in SJS and OCP tears (SJS > OCP) when compared to controls. Across all study groups, MMP-9 levels correlated strongly with MMP-8 and MPO levels and MMP-8 correlated with MPO but did not reach significance in SJS. There was no relationship between MMP-7 and MPO.
Conclusions
Since MMP-8 and MPO are produced by inflammatory cells, particularly neutrophils, the correlation data indicate that they may be the common source of elevated enzymes including MMP-9 in SJS and OCP tears. Elevated MMP/TIMP ratios and MMP activity suggest an imbalance in tear MMP regulation that may explain the predisposition of these patients to develop corneal melting and chronic complications associated with persistent inflammation. MPO in tears may be a sensitive and specific marker for the quantification of ocular inflammation.
doi:10.1016/j.ophtha.2013.06.049
PMCID: PMC3920830  PMID: 23962653
4.  Can a high acromion index predict rotator cuff tears? 
International Orthopaedics  2012;36(5):1019-1024.
Purpose
The purpose of this study was to identify the relationship between an acromion index (AI) and the size of a rotator cuff tear. The hypothesis of our study was that an AI will be higher in patients with a full-thickness tear than in patients with a partial-thickness articular-side tear, and that it can be used as a predictor for the size of a rotator cuff tear.
Methods
We included 284 patients who had been diagnosed with rotator cuff tears and had undergone arthroscopic rotator cuff repair at our institute. All patients were divided into five distinct groups (partial-thickness articular side tear, and four subgroups of full-thickness tears) depending on the size of the rotator cuff tear on arthroscopy. In each patient, an AI was measured on the pre-operative oblique coronal MR images and then analysed to determine the difference between groups.
Results
There were statistically significant differences between the partial-thickness articular side rotator cuff tear and large-to-massive rotator cuff tear groups (p < 0.01), and the mean value of an AI was highest in the large-sized full-thickness tear group. The AI of the partial-thickness articular-side rotator cuff tear group was statistically different from the large-to-massive rotator cuff tear groups.
Conclusions
The AI can be a predictor which can differentiate a partial-thickness articular-side tear and a large-to-massive rotator cuff tear pre-operatively. However the AI could not provide useful guidance on predicting the differences in tear size in full-thickness tear patients. We suggest that a high AI can be one of the associated factors for progression to large-to-massive rotator cuff tears in a rotator cuff disease.
doi:10.1007/s00264-012-1499-4
PMCID: PMC3337092  PMID: 22310972
Medicine & Public Health; Orthopedics
5.  Active synovial matrix metalloproteinase-2 is associated with radiographic erosions in patients with early synovitis 
Arthritis Research  2000;2(2):145-153.
Serum and synovial tissue expression of the matrix metalloproteinase (MMP)-2 and -9 and their molecular regulators, MMP-14 and TIMP-2 was examined in 28 patients with inflammatory early synovitis and 4 healthy volunteers and correlated with the presence of erosions in the patients. Immunohistological staining of MMP-2, MMP-14 and TIMP-2 localized to corresponding areas in the synovial lining layer and was almost absent in normal synovium. Patients with radiographic erosions had significantly higher levels of active MMP-2 than patients with no erosions, suggesting that activated MMP-2 levels in synovial tissue may be a marker for a more aggressive synovial lesion.
Introduction:
In cancer the gelatinases [matrix metalloproteinase (MMP)-2 and MMP-9] have been shown to be associated with tissue invasion and metastatic disease. In patients with inflammatory arthritis the gelatinases are expressed in the synovial membrane, and have been implicated in synovial tissue invasion into adjacent cartilage and bone. It is hypothesized that an imbalance between the activators and inhibitors of the gelatinases results in higher levels of activity, enhanced local proteolysis, and bone erosion.
Objectives:
To determine whether the expression and activity levels of MMP-2 and MMP-9, and their regulators MMP-14 and tissue inhibitor of metalloproteinase (TIMP), are associated with early erosion formation in patients with synovitis of recent onset.
Patients and method:
A subset of 66 patients was selected from a larger early synovitis cohort on the basis of tissue availability for the study of synovial tissue and serum gelatinase expression. Patients with peripheral joint synovitis of less than 1 years' duration were evaluated clinically and serologically on four visits over a period of 12 months. At the initial visit, patients underwent a synovial tissue biopsy of one swollen joint, and patients had radiographic evaluation of hands and feet initially and at 1year. Serum MMP-1, MMP-2, MMP-9, MMP-14, and TIMP-1 and TIMP-2 levels were determined, and synovial tissue was examined by immunohistology for the expression of MMP-2 and MMP-9, and their molecular regulators. Gelatinolytic activity for MMP-2 and MMP-9 was quantified using a sensitive, tissue-based gel zymography technique. Four healthy individuals underwent closed synovial biopsy and their synovial tissues were similarly analyzed.
Results:
Of the 66 patients studied, 45 fulfilled American College of Rheumatology criteria for rheumatoid arthritis (RA), with 32 (71%) being rheumatoid factor positive. Of the 21 non-RA patients, seven had a spondylarthropathy and 14 had undifferentiated arthritis. Radiographically, 12 of the RA patients had erosions at multiple sites by 1 year, whereas none of the non-RA patients had developed erosive disease of this extent. In the tissue, latent MMP-2 was widely expressed in the synovial lining layer and in areas of stromal proliferation in the sublining layer and stroma, whereas MMP-9 was expressed more sparsely and focally. MMP-14, TIMP-2, and MMP-2 were all detected in similar areas of the lining layer on consecutive histologic sections. Tissue expression of MMP-14, the activator for pro-MMP-2, was significantly higher in RA than in non-RA patients (8.4 ± 5 versus 3.7 ± 4 cells/high-power field; P = 0.009). In contrast, the expression of TIMP-2, an inhibitor of MMP-2, was lower in the RA than in the non-RA samples (25 ± 12 versus 39 ± 9 cells/high-power field; P = 0.01). Synovial tissue expressions of MMP-2, MMP-14, and TIMP-2 were virtually undetectable in normal synovial tissue samples. The synovial tissue samples of patients with erosive disease had significantly higher levels of active MMP-2 than did those of patients without erosions (Fig. 1). Tissue expression of MMP-2 and MMP-9, however, did not correlate with the serum levels of these enzymes.
With the exception of serum MMP-2, which was not elevated over normal, serum levels of all of the other MMPs and TIMPs were elevated to varying degrees, and were not predictive of erosive disease. Interestingly, MMP-1 and C-reactive protein, both of which were associated with the presence of erosions, were positively correlated with each other (r = 0.42; P < 0.001).
Discussion:
MMP-2 and MMP-9 are thought to play an important role in the evolution of joint erosions in patients with an inflammatory arthritis. Most studies have concentrated on the contribution of MMP-9 to the synovitis, because synovial fluid and serum MMP-9 levels are markedly increased in inflammatory arthropathies. Previously reported serum levels of MMP-9 have varied widely. In the present sample of patients with synovitis of recent onset, serum MMP-9 levels were elevated in only 21%. Moreover, these elevations were not specific for RA, the tissue expression of MMP-9 was focal, and the levels of MMP-9 activity were not well correlated with early erosions. Although serum MMP-2 levels were not of prognostic value, high synovial tissue levels of MMP-2 activity were significantly correlated with the presence of early erosions. This may reflect augmented activation of MMP-2 by the relatively high levels of MMP-14 and low levels of TIMP-2 seen in these tissues. We were able to localize the components of this trimolecular complex to the synovial lining layer in consecutive tissue sections, a finding that is consistent with their colocalization.
In conclusion, we have provided evidence that active MMP-2 complexes are detectable in the inflamed RA synovium and may be involved in the development of early bony erosions. These results suggest that strategies to inhibit the activation of MMP-2 may have the potential for retarding or preventing early erosions in patients with inflammatory arthritis.
PMCID: PMC17808  PMID: 11062605
early synovitis; erosion; metalloproteinase; matrix metalloproteinase-2; rheumatoid arthritis
6.  Matrix metalloproteases and their inhibitors are altered in torn rotator cuff tendons, but also in the macroscopically and histologically intact portion of those tendons 
Summary
We evaluated whether matrix metalloproteases and their inhibitors are involved in extracellular matrix remodelling and degradation of chronic rotator cuff tears. Tendon samples were harvested from 13 patients who underwent arthroscopic repair of a rotator cuff tear. Supraspinatus specimens were harvested en bloc from the arthroscopically intact middle portion of the tendon, more than 1 cm lateral to the torn edge, from the lateral edge of the tear, and from the superior margin of the macroscopically intact subscapularis tendon, used as control. The collagenases, the stromelysins, and the tissue inhibitors of metalloprotease arrays were analyzed blindly by multiplex sandwich ELISA in each specimen. Histological evidence of tendinopathy was present in all patients with a rotator cuff tear, but not in the macroscopically intact subscapularis tendon. There were significantly increased levels of MMP 1, MMP 2, MMP 3, TIMP-1, and TIMP-2 in all specimens examined, including the macroscopically intact portion of the supraspinatus tendon and the subscapularis (control specimens). The levels of specific matrix metalloproteases and their inhibitors are altered in torn rotator cuff tendons, but also in the macroscopically and histologically intact tendons. These changes extended medially to the site of tendon tear, and to other tendons.
PMCID: PMC3838321  PMID: 24367772
gene expression; rotator cuff; surgery; outcome
7.  Comparisons of the Various Partial-Thickness Rotator Cuff Tears on MR Arthrography and Arthroscopic Correlation 
Korean Journal of Radiology  2010;11(5):528-535.
Objective
To assess the diagnostic performance of MR arthrography in the diagnosis of the various types of partial-thickness rotator cuff tears by comparing the MR imaging findings with the arthroscopic findings.
Materials and Methods
The series of MR arthrography studies included 202 patients consisting of 100 patients with partial-thickness rotator cuff tears proved by arthroscopy and a control group of 102 patients with arthroscopically intact rotator cuffs, which were reviewed in random order. At arthroscopy, 54 articular-sided, 26 bursal-sided, 20 both articular- and bursal-sided partial-thickness tears were diagnosed. The MR arthrographies were analyzed by two radiologists for articular-sided tears, bursal-sided tears, and both articular- and bursal-sided tears of the rotator cuff. The sensitivity and specificity of each type of partial-thickness tears were determined. Kappa statistics was calculated to determine the inter- and intra-observer agreement of the diagnosis of partial-thickness rotator cuff tears.
Results
The sensitivity and specificity of the various types of rotator cuff tears were 85% and 90%, respectively for articular-sided tears, 62% and 95% for bursal-sided tears, as well as 45% and 99% for both articular- and bursal-sided tears. False-negative assessments were primarily observed in the diagnosis of bursal-sided tears. Conversely, both articular- and bursal-sided tears were overestimated as full-thickness tears. Inter-observer agreement was excellent for the diagnosis of articular-sided tears (k = 0.70), moderate (k = 0.59) for bursal-sided tears, and fair (k = 0.34) for both articular- and bursal-sided tears, respectively. Intra-observer agreement for the interpretation of articular- and bursal-sided tears was excellent and good, respectively, whereas intra-observer agreement for both articular- and bursal-sided tears was moderate.
Conclusion
MR arthrography is a useful diagnostic tool for partial-thickness rotator cuff tears, but has limitations in that it has low sensitivity in bursal- and both articular- and bursal-sided tears. In addition, it shows only fair inter-observer agreement when it comes to predicting both articular- and bursal-sided tears.
doi:10.3348/kjr.2010.11.5.528
PMCID: PMC2930161  PMID: 20808696
Shoulder; MR arthrography; Rotator cuff; Partial-thickness tear
8.  Partial-thickness articular surface rotator cuff tears in patients over the age of 35: Etiology and intra-articular associations 
Purpose:
Partial-thickness articular-sided rotator cuff tears have a multifactorial etiology and are associated with degeneration of the tendon. They are often described as an injury of the young athlete, although they are also found in the older population. The aim of this study was to investigate the frequency and associations of partial-thickness articular-sided tears in patients over the age of 35 years.
Design:
Retrospective
Materials and Methods:
A retrospective study of all arthroscopic procedures for rotator cuff pathology in patients over the age of 35 years over a 2-year period by a single surgeon was performed. The included patients were divided into two groups based on the arthroscopic findings: those with a partial-thickness articular-sided rotator cuff tear and those with pure tendinopathy. The groups were then compared to identify the associated pathology with the rotator cuff lesions. 2×2 contingency table analysis and unpaired Student's t-test were used for statistical analysis.
Results:
One hundred patients were included in the study of whom 62 had a partial articular-sided tear. Those with a partial articular-sided tear were older (P=0.0001), were more commonly associated with a documented injury (P=0.03), and more commonly had biceps degeneration (P=0.001) and synovitis (P=0.02) within the joint.
Conclusion:
Partial-thickness articular-sided tears are a common occurrence in patients requiring arthroscopic surgery for rotator cuff pathology over the age of 35 years. This probably reflects an injury in an already degenerate cuff. This would support the theory of intrinsic degeneration of the tendon in this age group and probably represent a different etiology to those seen in the young athletes.
Level of Evidence:
Level 3
doi:10.4103/0973-6042.94309
PMCID: PMC3326750  PMID: 22518075
Associated pathology; etiology; partial-thickness; rotator cuff tears
9.  Matrix metalloproteinases and tissue inhibitors of metalloproteinases in the aqueous humour of patients with primary angle closure glaucoma - a quantitative study 
BMC Ophthalmology  2014;14:33.
Background
Altered levels of specific matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in the aqueous humour of primary open-angle glaucoma (POAG) eyes have been described. In this study, levels of specific MMPs and TIMPs in the aqueous humour of primary angle-closure glaucoma (PACG) eyes were measured and compared with those of POAG as well as non-glaucoma control eyes.
Methods
Aqueous humour from 16 PACG, 28 POAG and 27 control eyes were sampled during intraocular surgery. Levels of total protein, MMP-2, MMP-3, TIMP-1 and TIMP-2 were quantified by protein assay and enzyme immunoassay.
Results
Total protein levels were significantly higher in PACG (0.426 ± 0.126 mg/ml, p = 0.043) and POAG (0.578 ± 0.360 mg/ml, p = 0.007) compared to controls (0.292 ± 0.192 mg/ml). The difference between PACG and POAG was not significant (p = 0.158). MMP-2 was significantly higher in PACG (p = 0.032) and POAG (p < 0.001) compared to controls. The difference between PACG and POAG was also not significant (p = 0.133). MMP-3 was significantly higher in POAG compared to controls (p = 0.002) and PACG (p = 0.029). The difference between PACG and controls was not significant (p = 0.962). TIMP-1 was significantly higher in PACG (p = 0.049) and POAG (p = 0.010) compared to controls. The difference between PACG and POAG was also not significant (p = 0.961). TIMP-2 was significantly higher in POAG (p = 0.004) compared to controls. The difference between PACG and either controls or POAG was not significant (p > 0.05). Although not statistically significant (p > 0.05), the MMP-2/TIMP-2 ratio was highest in PACG (2.83 ± 7.40), followed by POAG (1.38 ± 1.55) and controls (1.34 ± 3.05). Similarly, the MMP-2/TIMP-1 ratio was highest in PACG (1.50 ± 1.69), followed by POAG (1.40 ± 0.77) and controls (1.15 ± 0.92). The MMP-2 + MMP-3/TIMP-1 + TIMP-2 ratio was higher in PACG (0.83 ± 0.80) and POAG (0.82 ± 0.53) compared to controls (0.70 ± 0.63). In both POAG and PACG, there were no significant differences in the levels of total protein, MMP-2, MMP-3, TIMP-1 and TIMP-2 between patients on prostaglandin analogues and those not.
Conclusion
We found altered levels of MMPs and TIMPs as well as imbalance of MMP:TIMP ratios in the aqueous humour of PACG eyes that were different from POAG and non-glaucoma control eyes.
doi:10.1186/1471-2415-14-33
PMCID: PMC3994396  PMID: 24655889
Matrix metalloproteinases; Tissue inhibitors of metalloproteinases; Aqueous humour; Primary angle-closure glaucoma; Primary open-angle glaucoma
10.  Asymptomatic rotator cuff tears: Patient demographics and baseline shoulder function 
Background
The purpose of this study is to characterize the demographic features and physical function of subjects with asymptomatic rotator cuff tears and to compare their shoulder function to controls with an intact rotator cuff.
Materials and Methods
196 subjects with an asymptomatic rotator cuff tear and 54 subjects with an intact rotator cuff presenting with a painful rotator cuff tear in the contralateral shoulder were enrolled. Various demographic features, shoulder function (ASES score and SST score), range of motion and strength were compared.
Results
The demographic features of the study and control groups were similar. Hand dominance was associated with the presence of shoulder pain (p < .05). Subjects with an intact rotator cuff had greater but clinically insignificant ASES (p < .05) and SST scores (p < .05) than those with an asymptomatic tear.
No differences in functional scores, range of motion or strength were seen between partial (n=61) and full-thickness tears (n=135). Of the full-thickness tears, 36 (27%) were classified as small, 85 (63%) as medium and 14 (10%) as large tears. No differences were seen in functional scores between full-thickness tears of various sizes.
Conclusions
When asymptomatic, a rotator cuff tear is associated with a clinically insignificant loss of shoulder function compared to those with an intact rotator cuff. Therefore, a clinically detectable decline in shoulder function may indicate an “at-risk” asymptomatic tear. The presence of pain is important in cuff deficient shoulders for creating a measurable loss of shoulder function. Hand dominance appears to be an important risk factor for pain.
doi:10.1016/j.jse.2010.07.017
PMCID: PMC3725777  PMID: 21030274
Rotator cuff tear; asymptomatic; shoulder function; strength; normal shoulder; ultrasound
11.  Rotator Cuff Tear Pain and Tear Size and Scapulohumeral Rhythm 
Journal of Athletic Training  2009;44(2):148-159.
Context:
The body of knowledge concerning shoulder kinematics in patients with rotator cuff tears is increasing. However, the level of understanding regarding how pain and tear size affect these kinematic patterns is minimal.
Objective:
To identify relationships between pain associated with a full-thickness rotator cuff tear, tear size, and scapulohumeral rhythm (SHR) and to determine whether pain and tear size serve as predictors of SHR.
Design:
A test-retest design was used to quantify pain and SHR before and after a subacromial lidocaine injection. Correlation and multivariate analyses were used to identify relationships among pain, tear size, and SHR.
Setting:
Orthopaedic biomechanics research laboratory.
Patients or Other Participants:
Fifteen patients (age range, 40–75 years) with diagnosed full-thickness rotator cuff tears participated. They were experiencing pain at the time of testing.
Intervention(s):
Shoulder kinematic data were collected with an electromagnetic tracking system before and after the patient received a lidocaine injection.
Main Outcome Measure(s):
Pain was rated using a visual analog scale. Three-dimensional scapular kinematics and glenohumeral elevation were assessed. Scapular kinematics included anterior-posterior tilt, medial-lateral tilt, and upward-downward rotation. A regression model was used to calculate SHR (scapular kinematics to glenohumeral elevation) for phases of humeral elevation and lowering.
Results:
Linear relationships were identified between initial pain scores and SHR and between tear size and SHR, representing an increased reliance on scapular motion with increasing pain and tear size. Pain was identified as an independent predictor of SHR, whereas significant findings for the effect of tear size on SHR and the interaction between pain and tear size were limited.
Conclusions:
We noted an increased reliance on scapular contributions to overall humeral elevation with increasing levels of pain and rotator cuff tear size. Pain associated with a rotator cuff tear serves as a primary contributor to the kinematic patterns exhibited in patients with rotator cuff tears.
PMCID: PMC2657030  PMID: 19295959
shoulder kinematics; scapula; biomechanics
12.  Exercise therapy for the conservative management of full thickness tears of the rotator cuff: a systematic review 
Purpose: To review the evidence for the effectiveness of therapeutic exercise for the treatment of full thickness (including massive and inoperable) tears of the rotator cuff.
Relevance: There is little consensus as to the most effective treatment of full thickness and massive tears of the rotator cuff. There is consensus that the outcome of rotator cuff tendon surgery in the elderly is generally very poor. As such, exercise therapy is usually recommended for this patient group. Although commonly prescribed, the evidence to support this approach is equivocal. The aim of this study was to conduct a systematic review of the literature to determine the efficacy of exercise therapy for the management of full thickness rotator cuff tears.
Methods: A systematic review was conducted to synthesise the available research literature on the effectiveness of exercise therapy for full thickness tears of the rotator cuff.
Data source: Reports up to and including September 2006 were located from MEDLINE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), AMED, EMBASE, the Cochrane Database of Systematic Reviews and the Physiotherapy Evidence Database (PEDro) using the terms “rotator cuff” and “tear/s” and “exercise” or “physiotherapy” or “physical therapy” or “rehabilitation”.
Study selection: Studies were included if they related to full thickness rotator cuff tears and exercise.
Data extraction: Two independent reviewers assessed the methodological quality of the studies. Differences were resolved by consensus.
Analysis/Data synthesis: Ten studies met the inclusion criteria: eight were observational case series and two were single case studies. There were no randomised clinical trials.
Results: Four studies were specific to massive rotator cuff tears. One study had a sub‐group with massive cuff tears and five studies were not specific as to the size of the full thickness tear. Due to the heterogeneity of outcome measures used, it was not possible to combine results. In all studies an improvement in outcome scores was reported. Exercise programmes were well documented in five studies.
Conclusions: No randomised controlled trials met the inclusion criteria and the evaluation has been based on observational studies of lower scientific merit. The findings suggest that some evidence exists to support the use of exercise in the management of full thickness rotator cuff tears. There is a definite need for well‐planned randomised controlled trials investigating the efficacy of exercise in the management of full thickness and massive rotator cuff tears.
doi:10.1136/bjsm.2006.032524
PMCID: PMC2658945  PMID: 17264144
rotator cuff; exercise; rehabilitation; outcome
13.  Classification of rotator cuff tendinopathy using high definition ultrasound 
Summary
Background:
ultrasound is a valid cost effective tool in screening for rotator cuff pathology with high levels of accuracy in detecting full-thickness tears. To date there is no rotator cuff tendinopathy classification using ultrasound. The aims of this study are to define a valid high-definition ultrasound rotator cuff tendinopathy classification, which has discriminate validity between groups based upon anatomical principles.
Methods:
464 women, aged 65–87, from an established general population cohort underwent bilateral shoulder ultrasound and musculoskeletal assessment. Sonographer accuracy was established in a separate study by comparing ultrasound findings to the gold standard intra-operative findings.
Results:
there were 510 normal tendons, 217 abnormal tendons, 77 partial tears, and 124 full-thickness tears. There was no statistical difference in age or the proportion with pain between the abnormal enthesis and partial tear groups, however both groups were statistically older (p<0.001) and had a greater proportion with pain (p<0.001 & p=0.050) than normal tendons. The full-thickness tears were statistically older than normal tendons (p<0.001), but not abnormal/partially torn tendons. The proportion with pain was significantly greater than both groups (p<0.001 & p=0.006). Symptomatic shoulders had a larger median tear size than asymptomatic shoulders (p=0.006). Using tear size as a predictor of pain likelihood, optimum sensitivity and specificity occurred when dividing tears into groups up to 2.5cm and >2.5cm, which corresponds with anatomical descriptions of the width of the supraspinatus tendon.
Conclusion:
the classification system is as follows: Normal Tendons; Abnormal enthesis/Partial-thickness tear; Single tendon full-thickness tears (0–2.5cm); Multi-tendon full-thickness tears (>2.5cm).
PMCID: PMC4241433  PMID: 25489559
classification; rotator cuff; high-definition ultrasound
14.  Systematic Review: What Surgical Technique Provides the Best Outcome for Symptomatic Partial Articular-Sided Rotator Cuff Tears? 
The Iowa Orthopaedic Journal  2012;32:164-172.
Purpose
There is no consensus in the literature regarding the optimal surgical treatment of symptomatic partial rotator cuff tears. We attempted to determine the optimal surgical treatment for partial articular-sided rotator cuff tears through a systematic review of appropriate studies.
Methods
Medline®, PubMed, Ovid, and the cochrane register of controlled trials were searched for all studies published between January 1991 to March 2010 that used the key words “shoulder”, “partial rotator cuff tear”, “PASTA”, “articularsided rotator cuff tear”, “incomplete rotator cuff tear”, “arthroscopic” and “repair”. Inclusion criteria were studies (Level I to IV) that reported clinical outcomes in patients who had arthroscopic evaluation and arthroscopic or mini-open treatment of a symptomatic partial articular-sided rotator cuff tear. One of three surgical treatments was used: debridement with or without acromioplasty; transtendon arthroscopic repair; or tear completion with repair. Exclusion criteria included studies with over 50% overhead throwers or athletes, studies that involved an open approach to the rotator cuff without arthroscopy, and data presented in technical notes or review papers. Data abstracted from the studies included patient demographics, tear characteristics, surgical procedure(s), and clinical outcomes.
Results
Of 588 studies involving partial rotator cuff tears, 14 studies were identified which met our inclusion and exclusion criteria. All studies were Level IV retrospective case-series studies. Seven studies reported outcomes after rotator cuff debridement. Tear completion and repair was performed in three studies. Transtendon repair of a partial articular-sided rotator cuff tear was performed in three studies. Although different outcome measures were used, each study reported subjective and objective improvement postoperatively. One study compared outcomes in patients who underwent arthroscopic debridement versus another group where patients had tear completion and mini-open repair. Improved long-term results and decreased reoperation rates were reported in the tear completion and repair group.
Conclusion
On the basis of the available evidence, no single technique provides superior clinical outcomes. Level I and II comparison studies are needed to determine the optimal treatment of partial articular-sided rotator cuff tears.
PMCID: PMC3565397  PMID: 23576937
15.  Incidence of familial tendon dysfunction in patients with full-thickness rotator cuff tears 
Background
A familial predisposition to the development of rotator cuff tearing has been previously reported. Very little information exists on the development of global tendon dysfunction in patients with rotator cuff tears. The purpose of the current study was to determine the incidence of global tendon dysfunction as well as the need for surgery for tendon dysfunction in patients with rotator cuff tears and their family members and compare them to age-matched controls.
Methods
Ninety two patients with full-thickness rotator cuff tears and 92 age-matched controls with no history of shoulder dysfunction or surgery responded to several questions regarding tendon diseases in themselves as well as their family members. Individuals were queried regarding the presence of tendon diseases other than the rotator cuff, the need for surgery on these other tendinopathies, the presence of family members having tendinopathies including rotator cuff disease, and the need for family members to have surgery for these problems. Chi-square analysis was performed to compare the incidences between cases and controls (P<0.05 was considered significant).
Results
The average age of patients in the rotator cuff tear group and control groups were 58.24±7.4 and 58.42±8.5 years, respectively (P=0.876). Results showed 32.3% of patients in the rotator cuff tear group reported that family members had a history of rotator cuff problems or surgery compared to only 18.3% of the controls (P=0.035), and 38.7% of patients in the rotator cuff tear group reported they had a history of other tendon problems compared to only 19.3% of individuals in the control group (P=0.005).
Conclusion
Individuals with rotator cuff tears report a higher incidence of family members having rotator cuff problems or surgery as well as a higher incidence of other tendinopathies compared to controls. This data further supports a familial predilection for the development of rotator cuff tearing and generalized tendinopathies.
doi:10.2147/OAJSM.S63656
PMCID: PMC4043799  PMID: 24966704
family history; tendinopathies
16.  Serum TIMP-1, TIMP-2, and MMP-1 in patients with systemic sclerosis, primary Raynaud's phenomenon, and in normal controls 
Annals of the Rheumatic Diseases  2001;60(9):846-851.
BACKGROUND—Excess tissue matrix accumulates in systemic sclerosis (SSc), accounting for both visceral and dermal fibrosis. It is suggested that decreased serum levels of matrix metalloproteinases (MMPs) or increased levels of tissue inhibitors of matrix metalloproteinases (TIMPs) may account for this matrix accumulation.
OBJECTIVE—To measure serum levels of tissue inhibitors of metalloproteinases, TIMP-1, TIMP-2, and collagenase-1 (MMP-1), in patients with diffuse cutaneous systemic sclerosis (dcSSc), limited cutaneous systemic sclerosis (lcSSc), primary Raynaud's phenomenon (RP), and in normal controls.
METHODS—Serum samples from patients with dcSSc (n=83), lcSSc (n=87), RP (n=80), and normal controls (n=98) were analysed using enzyme linked immunosorbent assays (ELISAs) for total TIMP-1, TIMP-2, and MMP-1. Results from each assay were analysed by the Kruskal-Wallis test. Dunn's multiple comparison post-test was then applied between groups.
RESULTS—TIMP-1 levels were significantly raised in dcSSc and lcSSc groups compared with the RP group and normal controls (p<0.01 to p<0.001). In the dcSSc group, TIMP-1 levels were significantly higher in early disease (<2 years) than in late stage disease (>4 years) (p<0.05). This was not found for the lcSSc group. Serum TIMP-2 and MMP-1 levels in dcSSc and lcSSc did not differ significantly from those in normal controls. Increased levels of TIMPs were not convincingly associated with organ disease. No assay result correlated with autoantibody status (anti-topoisomerase 1 (anti-Scl-70), anticentromere antibody, or anti-RNA polymerase). No significant differences in serum TIMP-1, TIMP-2, or MMP-1 levels were shown in the RP group compared with normal controls.
CONCLUSIONS—Raised TIMP-1 levels in the SSc groups support the hypothesis that matrix accumulation occurs in SSc at least in part owing to decreased degradation. Moreover, the variation in TIMP-1 levels between the early and late disease stages of dcSSc seems to reflect the early progressive course of dermal fibrosis seen clinically. The expected reduction in serum MMP-1 levels in the SSc groups was not found. This suggests that tissue matrix accumulation is due to increased inhibitors rather than to decreased MMPs.


PMCID: PMC1753839  PMID: 11502611
17.  The association between retraction of the torn rotator cuff and increasing expression of hypoxia inducible factor 1α and vascular endothelial growth factor expression: an immunohistological study 
Background
Differing levels of tendon retraction are found in full-thickness rotator cuff tears. The pathophysiology of tendon degeneration and retraction is unclear. Neoangiogenesis in tendon parenchyma indicates degeneration. Hypoxia inducible factor 1α (HIF) and vascular endothelial growth factor (VEGF) are important inducers of neoangiogenesis. Rotator cuff tendons rupture leads to fatty muscle infiltration (FI) and muscle atrophy (MA). The aim of this study is to clarify the relationship between HIF and VEGF expression, neoangiogenesis, FI, and MA in tendon retraction found in full-thickness rotator cuff tears.
Methods
Rotator cuff tendon samples of 33 patients with full-thickness medium-sized rotator cuff tears were harvested during reconstructive surgery. The samples were dehydrated and paraffin embedded. For immunohistological determination of VEGF and HIF expression, sample slices were strained with VEGF and HIF antibody dilution. Vessel density and vessel size were determined after Masson-Goldner staining of sample slices. The extent of tendon retraction was determined intraoperatively according to Patte's classification. Patients were assigned to 4 categories based upon Patte tendon retraction grade, including one control group. FI and MA were measured on standardized preoperative shoulder MRI.
Results
HIF and VEGF expression, FI, and MA were significantly higher in torn cuff samples compared with healthy tissue (p < 0.05). HIF and VEGF expression, and vessel density significantly increased with extent of tendon retraction (p < 0.05). A correlation between HIF/VEGF expression and FI and MA could be found (p < 0.05). There was no significant correlation between HIF/VEGF expression and neovascularity (p > 0.05)
Conclusion
Tendon retraction in full-thickness medium-sized rotator cuff tears is characterized by neovascularity, increased VEGF/HIF expression, FI, and MA. VEGF expression and neovascularity may be effective monitoring tools to assess tendon degeneration.
doi:10.1186/1471-2474-11-230
PMCID: PMC2958987  PMID: 20932296
18.  The Factors Affecting the Clinical Outcome and Integrity of Arthroscopically Repaired Rotator Cuff Tears of the Shoulder 
Clinics in Orthopedic Surgery  2009;1(2):96-104.
Background
The purpose of this study was to evaluate the functional and anatomic results of arthroscopic rotator cuff repair, and to analyze the factors affecting the integrity of arthroscopically repaired rotator cuff tears of the shoulder.
Methods
One hundred sixty-nine consecutive shoulders that underwent arthroscopic rotator cuff repair, had a postoperative MRI evaluation and were followed for at least two years were enrolled in this study. The mean age was 57.6 years (range, 38 to 74 years) and the mean follow-up period was 39 months (range, 24 to 83 months).
Results
The rotator cuff was completely healed in 131 (77.5%) out of 169 shoulders and recurrent tears occurred in 38 shoulders (22.5%). At the last follow-up visit, the mean score for pain during motion was 1.53 (range, 0 to 4) in the completely healed group and 1.59 (range, 0 to 4) in the group with recurrent tears (p = 0.092). The average elevation strength was 7.87 kg (range, 4.96 to 11.62 kg) and 5.25 kg (range, 4.15 to 8.13 kg) and the mean University of California at Los Angeles score was 30.96 (range, 26 to 35) and 30.64 (range, 23 to 34), respectively (p < 0.001, p = 0.798). The complete healing rate was 87.8% in the group less than 50 years of age (49 shoulders), 79.4% in the group over 51 years but less than 60 years of age (68 shoulders), and 65.4% in the group over 61 years of age (52 shoulders, p = 0.049); it was 96.7% in the group with small-sized tears (30 shoulders), 87.3% in the group with medium-sized tears (71 shoulders), and 58.8% in the group with large-sized or massive tears (68 shoulders, p = 0.009). All of the rotator cuffs with a global fatty degeneration index of greater than two preoperatively had recurrent tears.
Conclusions
Arthroscopic repair of full-thickness rotator cuff tears led to a relatively high rate of recurrent defects. However, the minimum two-year follow up demonstrated excellent pain relief and improvement in the ability to perform the activities of daily living, despite the structural failures. The factors affecting tendon healing were the patient's age, the size and extent of the tear, and the presence of fatty degeneration in the rotator cuff muscle.
doi:10.4055/cios.2009.1.2.96
PMCID: PMC2766755  PMID: 19885061
Shoulder; Rotator cuff tear; Arthroscopic repair; Repair integrity; Retear
19.  Predictors of Pain and Function in Patients With Symptomatic, Atraumatic Full-Thickness Rotator Cuff Tears 
Background
Although the prevalence of full-thickness rotator cuff tears increases with age, many patients are asymptomatic and may not require surgical repair. The factors associated with pain and loss of function in patients with rotator cuff tears are not well defined.
Purpose
To determine which factors correlate with pain and loss of function in patients with symptomatic, atraumatic full-thickness rotator cuff tears who are enrolled in a structured physical therapy program.
Study Design
Cross-sectional study; Level of evidence, 3.
Methods
A multicenter group enrolled patients with symptomatic, atraumatic rotator cuff tears in a prospective, nonrandomized cohort study evaluating the effects of a structured physical therapy program. Time-zero patient data were reviewed to test which factors correlated with Western Ontario Rotator Cuff (WORC) index and American Shoulder and Elbow Surgeons (ASES) scores.
Results
A total of 389 patients were enrolled. Mean ASES score was 53.9; mean WORC score was 46.9. The following variables were associated with higher WORC and ASES scores: female sex (P = .001), education level (higher education, higher score; P <.001), active abduction (degrees; P = .021), and strength in forward elevation (P = .002) and abduction (P = .007). The following variables were associated with lower WORC and ASES scores: male sex (P = .001), atrophy of the supraspinatus (P = .04) and infraspinatus (P = .003), and presence of scapulothoracic dyskinesia (P < .001). Tear size was not a significant predictor (WORC) unless comparing isolated supraspinatus tears to supraspinatus, infraspinatus, and subscapularis tears (P = .004). Age, tear retraction, duration of symptoms, and humeral head migration were not statistically significant.
Conclusion
Nonsurgically modifiable factors, such as scapulothoracic dyskinesia, active abduction, and strength in forward elevation and abduction, were identified that could be addressed nonoperatively with therapy. Therefore, physical therapy for patients with symptomatic rotator cuff tears should target these modifiable factors associated with pain and loss of function.
doi:10.1177/0363546511426003
PMCID: PMC3632074  PMID: 22095706
rotator cuff tear; nonoperative treatment; WORC score; ASES score
20.  Differential Regulation of Matrix-Metalloproteinases and Their Tissue Inhibitors in Patients with Aneurysmal Subarachnoid Hemorrhage 
PLoS ONE  2013;8(3):e59952.
Background
Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in vascular remodeling, (neuro)inflammation, blood-brain barrier breakdown and neuronal apoptosis. Proinflammatory mechanisms are suggested to play an important role during early brain injury and cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). This study aimed to analyze MMP-3, MMP-9, TIMP-1 and TIMP-3 in patients with SAH and their respective association with cerebral vasospasm (CVS).
Methods
Blood samples were collected in 20 SAH patients on days 1 to 7, 9, 11, 13 and 15 and 20 healthy age and gender matched volunteers. Serum MMPs and TIMPs were analyzed using enzyme-linked immunosorbent assay. Doppler sonographic CVS was defined as a mean blood flow velocity above 120 cm/sec in the middle cerebral artery. When discharged from hospital and at 6 month follow-up neurological outcome was evaluated using the Glasgow Outcome Score and the modified Rankin Scale.
Results
MMP-9 was higher in SAH patients compared to healthy controls (p<0.001). Patients with CVS (n = 11) had elevated MMP-9 serum levels compared to patients without CVS (n = 9, p<0.05). Higher MMP-9 was observed in the presence of cerebral ischemia associated with cerebral vasospasm (p<0.05). TIMP-1 was increased in patients with SAH on day 4 (p<0.05). There was an imbalance of the MMP-9/TIMP-1 ratio in favor of MMP-9 in SAH patients, in particular those with CVS (p<0.001). MMP-3 and TIMP-3 were significantly lower in SAH patients throughout day 4 and day 7, respectively (p<0.05). We did not find an association between MMP-, TIMP levels and neurological outcome after 6 months.
Conclusions
MMP-3 and -9 are differentially regulated in SAH patients with both enzymes showing peak levels correlating with the development of CVS. The inhibitors TIMP-1 and -3 were low during the acute phase after SAH and increased later on which might suggest a preponderance of pro-inflammatory mechanisms.
doi:10.1371/journal.pone.0059952
PMCID: PMC3610709  PMID: 23555845
21.  Altered Circulating Levels of Matrix Metalloproteinases and Inhibitors Associated with Elevated Type 2 Cytokines in Lymphatic Filarial Disease 
Background
Infection with Wuchereria bancrofti can cause severe disease characterized by subcutaneous fibrosis and extracellular matrix remodeling. Matrix metalloproteinases (MMPs) are a family of enzymes governing extracellular remodeling by regulating cellular homeostasis, inflammation, and tissue reorganization, while tissue-inhibitors of metalloproteinases (TIMPs) are endogenous regulators of MMPs. Homeostatic as well as inflammation-induced balance between MMPs and TIMPs is considered critical in mediating tissue pathology.
Methods
To elucidate the role of MMPs and TIMPs in filarial pathology, we compared the plasma levels of a panel of MMPs, TIMPs, other pro-fibrotic factors, and cytokines in individuals with chronic filarial pathology with (CP Ag+) or without (CP Ag−) active infection to those with clinically asymptomatic infections (INF) and in those without infection (endemic normal [EN]). Markers of pathogenesis were delineated based on comparisons between the two actively infected groups (CP Ag+ compared to INF) and those without active infection (CP Ag− compared to EN).
Results and Conclusion
Our data reveal that an increase in circulating levels of MMPs and TIMPs is characteristic of the filarial disease process per se and not of active infection; however, filarial disease with active infection is specifically associated with increased ratios of MMP1/TIMP4 and MMP8/TIMP4 as well as with pro-fibrotic cytokines (IL-5, IL-13 and TGF-β). Our data therefore suggest that while filarial lymphatic disease is characterized by a non-specific increase in plasma MMPs and TIMPs, the balance between MMPs and TIMPs is an important factor in regulating tissue pathology during active infection.
Author Summary
Lymphatic filariasis afflicts over 120 million people worldwide. While the infection is mostly clinically asymptomatic, approximately 40 million people suffer from overt, morbid clinical pathology characterized by swelling of the scrotal area and lower limbs (hydrocele and lymphedema). Host immunologic factors that influence the pathogenesis of disease in these individuals are not completely understood. Matrix metalloproteinases are a family of circulating and tissue proteins that influence the development of tissue fibrosis. They are regulated by another family of proteins called tissue inhibitors of metalloproteinases. The interplay between these proteins governs tissue fibrosis in a variety of conditions. In addition, certain cytokines are known to promote pro-fibrotic events. We have attempted to elucidate the role of the above-mentioned factors in disease pathogenesis by comparing the plasma levels of the various markers in four groups of individuals: chronic pathology individuals with or without active filarial infection; asymptomatic, filaria-infected individuals; and uninfected, endemic normal individuals. We show that altered ratios of the metalloproteinases and their inhibitors—as well as elevated levels of pro-fibrotic cytokines—characterize filarial infection-induced lymphatic pathology.
doi:10.1371/journal.pntd.0001681
PMCID: PMC3367978  PMID: 22679524
22.  Plasma levels of the MMP-9:TIMP-1 complex as prognostic biomarker in breast cancer: a retrospective study 
BMC Cancer  2013;13:598.
Background
Worldwide more than one million women are annually diagnosed with breast cancer. A considerable fraction of these women receive systemic adjuvant therapy; however, some are cured by primary surgery and radiotherapy alone. Prognostic biomarkers guide stratification of patients into different risk groups and hence improve management of breast cancer patients. Plasma levels of Matrix Metalloproteinase-9 (MMP-9) and its natural inhibitor Tissue inhibitor of metalloproteinase-1 (TIMP-1) have previously been associated with poor patient outcome and resistance to certain forms of chemotherapy. To pursue additional prognostic information from MMP-9 and TIMP-1, the level of the MMP-9 and TIMP-1 complex (MMP-9:TIMP-1) was investigated in plasma from breast cancer patients.
Methods
Detection of protein:protein complexes in plasma was performed using a commercially available ELISA kit and, for the first time, the highly sensitive in-solution proximity ligation assay (PLA). We screened plasma from 465 patients with primary breast cancer for prognostic value of the MMP-9:TIMP-1 complex. Both assays were validated and applied for quantification of MMP-9:TIMP-1 concentration. In this retrospective study, we analyzed the association between the concentration of the MMP-9:TIMP-1 complex and clinicopathological data and disease free survival (DFS) in univariate and multivariate survival analyses.
Results
Following successful validation both assays were applied for MMP-9:TIMP-1 measurements. Of the clinicopathological parameters, only menopausal status demonstrated significant association with the MMP-9:TIMP-1 complex; P = 0.03 and P = 0.028 for the ELISA and PLA measurements, respectively. We found no correlation between the MMP-9:TIMP-1 protein complex and DFS neither in univariate nor in multivariate survival analyses.
Conclusions
Despite earlier reports linking MMP-9 and TIMP-1 with prognosis in breast cancer patients, we here demonstrate that plasma levels of the MMP-9:TIMP-1 protein complex hold no prognostic information in primary breast cancer as a stand-alone marker. We demonstrate that the highly sensitive in-solution PLA can be employed for measurements of protein:protein complexes in plasma.
doi:10.1186/1471-2407-13-598
PMCID: PMC3878682  PMID: 24330623
Breast cancer; Plasma MMP-9:TIMP-1 complex; Proximity ligation assay; ELISA
23.  Relationship between clinical and surgical findings and reparability of large and massive rotator cuff tears: a longitudinal study 
Background
The literature has shown good results with partial repairs of large and massive tears of rotator cuff but the role of factors that affect reparability is less clear. The purpose of this study was twofold, 1) to examine clinical outcomes following complete or partial repair of large or massive full-thickness rotator cuff tear, and 2) to explore the value of clinical and surgical factors in predicting reparability.
Methods
This was a secondary data analysis of consecutive patients with large or massive rotator cuff tear who required surgical treatment (arthroscopic complete or partial repair) and were followed up for two years. Disability measures included the American Shoulder and Elbow Surgeons (ASES), the relative Constant-Murley score (CMS) and the shortened version of the Western Ontario Rotator Cuff Index (ShortWORC). The relationship between predictors and reparability was examined through logistic regressions and chi-square statistics as appropriate. Within group change over time and between group differences in disability outcomes, range of motion and strength were examined by student’s T-tests and non-parametric statistics.
Results
One hundred and twenty two patients (41 women, 81 men, mean age 64, SD = 9) were included in the analysis. There were 86 large (39 fully reparable, 47 partially reparable) and 36 (10 fully reparable, 26 partially reparable) massive tears. Reparability was not associated with age, sex, or pre-operative active flexion or abduction (p > 0.05) but the fully reparable tear group showed a better pre-operative ASES score (p = 0.01) and better active external rotation in neutral (p = 0.01). Reparability was associated with tear shape (p < 0.0001), size (p = 0.002), and tendon quality (p < 0.0001).
Conclusions
Reparability of large or massive tears is affected by a number of clinical and surgical factors. Patients whose tears could not be fully repaired showed a statistically significant improvement in range of motion, strength and disability at 2 years, although they had slightly inferior results compared to those with complete repairs.
doi:10.1186/1471-2474-15-180
PMCID: PMC4039058  PMID: 24884835
Large; Massive; Rotator cuff tear; Partial repair; Predictors
24.  Association between Serum Tissue Inhibitor of Matrix Metalloproteinase-1 Levels and Mortality in Patients with Severe Brain Trauma Injury 
PLoS ONE  2014;9(4):e94370.
Objective
Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) play a role in neuroinflammation after brain trauma injury (TBI). Previous studies with small sample size have reported higher circulating MMP-2 and MMP-9 levels in patients with TBI, but no association between those levels and mortality. Thus, the aim of this study was to determine whether serum TIMP-1 and MMP-9 levels are associated with mortality in patients with severe TBI.
Methods
This was a multicenter, observational and prospective study carried out in six Spanish Intensive Care Units. Patients with severe TBI defined as Glasgow Coma Scale (GCS) lower than 9 were included, while those with Injury Severity Score (ISS) in non-cranial aspects higher than 9 were excluded. Serum levels of TIMP-1, MMP-9 and tumor necrosis factor (TNF)-alpha, and plasma levels of tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 plasma were measured in 100 patients with severe TBI at admission. Endpoint was 30-day mortality.
Results
Non-surviving TBI patients (n = 27) showed higher serum TIMP-1 levels than survivor ones (n = 73). We did not find differences in MMP-9 serum levels. Logistic regression analysis showed that serum TIMP-1 levels were associated 30-day mortality (OR = 1.01; 95% CI = 1.001–1.013; P = 0.03). Survival analysis showed that patients with serum TIMP-1 higher than 220 ng/mL presented increased 30-day mortality than patients with lower levels (Chi-square = 5.50; P = 0.02). The area under the curve (AUC) for TIMP-1 as predictor of 30-day mortality was 0.73 (95% CI = 0.624–0.844; P<0.001). An association between TIMP-1 levels and APACHE-II score, TNF- alpha and TF was found.
Conclusions
The most relevant and new findings of our study, the largest series reporting data on TIMP-1 and MMP-9 levels in patients with severe TBI, were that serum TIMP-1 levels were associated with TBI mortality and could be used as a prognostic biomarker of mortality in TBI patients.
doi:10.1371/journal.pone.0094370
PMCID: PMC3984169  PMID: 24728097
25.  Increased Levels of Leukocyte-Derived MMP-9 in Patients with Stable Angina Pectoris 
PLoS ONE  2011;6(4):e19340.
Objective
There is a growing interest for matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) in plasma as novel biomarkers in coronary artery disease (CAD). We aimed to identify the sources of MMP-8, MMP-9, TIMP-1 and TIMP-2 among peripheral blood cells and further explore whether gene expression or protein release was altered in patients with stable angina pectoris (SA).
Methods
In total, plasma MMP-9 was measured in 44 SA patients and 47 healthy controls. From 10 patients and 10 controls, peripheral blood mononuclear cells (PBMC) and neutrophils were isolated and stimulated ex vivo. MMPs, TIMPs and myeloperoxidase were measured in plasma and supernatants by ELISA. The corresponding gene expression was measured by real-time PCR.
Results
Neutrophils were the dominant source of MMP-8 and MMP-9. Upon moderate stimulation with IL-8, the neutrophil release of MMP-9 was higher in the SA patients compared with controls (p<0.05). In PBMC, the TIMP-1 and MMP-9 mRNA expression was higher in SA patients compared with controls, p<0.01 and 0.05, respectively. There were no differences in plasma levels between patients and controls except for TIMP-2, which was lower in patients, p<0.01.
Conclusion
Measurements of MMPs and TIMPs in plasma may be of limited use. Despite similar plasma levels in SA patients and controls, the leukocyte-derived MMP-9 and TIMP-1 are significantly altered in patients. The findings indicate that the leukocytes are more prone to release and produce MMP-9 in symptomatic and angiographically verified CAD—a phenomenon that may have clinical implications in the course of disease.
doi:10.1371/journal.pone.0019340
PMCID: PMC3084822  PMID: 21559401

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